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Cell Rep. 2018 May 22;23(8):2467-2481. doi: 10.1016/j.celrep.2018.04.092.

Activation of the Arterial Program Drives Development of Definitive Hemogenic Endothelium with Lymphoid Potential.

Author information

1
National Primate Research Center, University of Wisconsin Graduate School, 1220 Capitol Court, Madison, WI 53715, USA.
2
Morgridge Institute for Research, 330 N. Orchard Street, Madison, WI 53715, USA; Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53707-7365, USA; Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA 93106, USA.
3
National Primate Research Center, University of Wisconsin Graduate School, 1220 Capitol Court, Madison, WI 53715, USA; Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53707-7365, USA; Department of Pathology and Laboratory Medicine, University of Wisconsin Medical School, 600 Highland Avenue, Madison, WI 53792, USA. Electronic address: islukvin@wisc.edu.

Abstract

Understanding the pathways guiding the development of definitive hematopoiesis with lymphoid potential is essential for advancing human pluripotent stem cell (hPSC) technologies for the treatment of blood diseases and immunotherapies. In the embryo, lymphoid progenitors and hematopoietic stem cells (HSCs) arise from hemogenic endothelium (HE) lining arteries but not veins. Here, we show that activation of the arterial program through ETS1 overexpression or by modulating MAPK/ERK signaling pathways at the mesodermal stage of development dramatically enhanced the formation of arterial-type HE expressing DLL4 and CXCR4. Blood cells generated from arterial HE were more than 100-fold enriched in T cell precursor frequency and possessed the capacity to produce B lymphocytes and red blood cells expressing high levels of BCL11a and β-globin. Together, these findings provide an innovative strategy to aid in the generation of definitive lymphomyeloid progenitors and lymphoid cells from hPSCs for immunotherapy through enhancing arterial programming of HE.

KEYWORDS:

ETS1; MAPK/ERK signaling; T cells; hematopoiesis; hematopoietic stem cells; hemogenic endothelium; human pluripotent stem cells

PMID:
29791856
PMCID:
PMC6410360
[Available on 2019-05-22]
DOI:
10.1016/j.celrep.2018.04.092
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